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1.
Eur Rev Med Pharmacol Sci ; 25(21): 6797-6812, 2021 11.
Article in English | MEDLINE | ID: covidwho-1524867

ABSTRACT

Cytokines in cardiac tissue plays a key role in progression of cardiometabolic diseases and cardiotoxicity induced by several anticancer drugs. Interleukin-1ß is one on the most studied regulator of cancer progression, survival and resistance to anticancer treatments. Recent findings indicate that interleukin1-ß exacerbates myocardial damages in cancer patients treated with chemotherapies and immune check-point inhibitors. Interleukin1-ß blocking agent canakinumab reduces major adverse cardiovascular events and cardiovascular death in recent cardiovascular trials. We focalized on the main biological functions of interleukin1-ß in cancer and cardiovascular diseases, summarizing the main clinical evidence available to date in literature. Especially in the era of SARS-CoV-2 infection, associated to coagulopathies, myocarditis and heart failure, cancer patients have an increased risk of cardiovascular complications compared to general population, therefore, the pharmacological inhibition of interleukin1-ß should be discussed and considered.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents/adverse effects , COVID-19/complications , Cardiotoxicity/prevention & control , Interleukin-1beta/metabolism , Neoplasms/drug therapy , Anthracyclines/adverse effects , Anthracyclines/therapeutic use , Antibodies, Monoclonal, Humanized/immunology , Antineoplastic Agents/therapeutic use , COVID-19/virology , Cardiotoxicity/etiology , Cardiovascular Diseases/prevention & control , Humans , Interleukin-1beta/immunology , Neoplasms/complications , SARS-CoV-2/isolation & purification
2.
Curr Oncol Rep ; 23(7): 79, 2021 05 03.
Article in English | MEDLINE | ID: covidwho-1384599

ABSTRACT

PURPOSE OF REVIEW: Immune checkpoint inhibitors (ICIs) have improved the survival of several cancers. However, they may cause a wide range of immune-related adverse events (irAEs). While most irAEs are manageable with temporary cessation of ICI and immunosuppression, cardiovascular toxicity can be associated with high rates of morbidity and mortality. As ICIs evolve to include high-risk patients with preexisting cardiovascular risk factors and disease, the risk and relevance of ICI-associated cardiotoxicity may be even higher. RECENT FINDINGS: Several cardiovascular toxicities such as myocarditis, stress cardiomyopathy, and pericardial disease have been reported in association with ICIs. Recent findings also suggest an increased risk of atherosclerosis with ICI use. ICI-associated myocarditis usually occurs early after initiation and can be fulminant. A high index of suspicion is required for timely diagnosis. Prompt treatment with high-dose corticosteroids is shown to improve outcomes. Although the overall incidence is rare, ICI cardiotoxicity, particularly myocarditis, is associated with significant morbidity and mortality, making it a major therapy-limiting adverse event. Early recognition and prompt treatment with the cessation of ICI therapy and initiation of high-dose corticosteroids are crucial to improve outcomes. Cardio-oncologists will need to play an important role not just in the management of acute cardiotoxicity but also to reduce the risk of long-term sequelae.


Subject(s)
Atherosclerosis/diagnosis , Cardiotoxicity/diagnosis , Immune Checkpoint Inhibitors/therapeutic use , Myocarditis/diagnosis , Neoplasms/drug therapy , Atherosclerosis/chemically induced , Atherosclerosis/immunology , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19/virology , Cardiotoxicity/etiology , Cardiotoxicity/immunology , Humans , Immune Checkpoint Inhibitors/adverse effects , Immune Checkpoint Inhibitors/immunology , Myocarditis/chemically induced , Myocarditis/immunology , Neoplasms/immunology , Pandemics , Risk Factors , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology
5.
Clin Rheumatol ; 40(4): 1649-1657, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1064518

ABSTRACT

In the early stage of the COVID-19 pandemic, Belgian health authorities endorsed the interim guidelines for the treatment of COVID-19 pneumonia: hydroxychloroquine (HCQ) recommended for treatment of hospitalized patients with moderate to severe disease. As a growing number of patients were admitted, inevitably, our internal medicine team questioned the efficacy and safety of HCQ, especially with regard to cardiac side effects. In parallel with our concerns, data regarding the safety and efficacy of HCQ were published, with discordant results and debate in the medical community. Media coverage of the possible risks and benefits of HCQ use in COVID-19 also caused confusion amongst the public. In this Perspectives in Rheumatology article, we review the use and safety of HCQ in autoimmune disease and its putative efficacy and toxicity in COVID-19. Finally, we share our concern about the future of this widely used and inexpensive drug after the COVID-19 pandemic has passed.


Subject(s)
Autoimmune Diseases/drug therapy , COVID-19/drug therapy , Cardiotoxicity/etiology , Hydroxychloroquine/adverse effects , Antiviral Agents/therapeutic use , Humans , Hydroxychloroquine/therapeutic use , Lupus Erythematosus, Systemic/drug therapy , Randomized Controlled Trials as Topic , Treatment Outcome
6.
Life Sci ; 269: 119099, 2021 Mar 15.
Article in English | MEDLINE | ID: covidwho-1036398

ABSTRACT

AIMS: Azithromycin is widely used broad spectrum antibiotic recently used in treatment protocol of COVID-19 for its antiviral and immunomodulatory effects combined with Hydroxychloroquine or alone. Rat models showed that Azithromycin produces oxidative stress, inflammation, and apoptosis of myocardial tissue. Rosuvastatin, a synthetic statin, can attenuate myocardial ischemia with antioxidant and antiapoptotic effects. This study aims to evaluate the probable protective effect of Rosuvastatin against Azithromycin induced cardiotoxicity. MAIN METHOD: Twenty adult male albino rats were divided randomly into four groups, five rats each control, Azithromycin, Rosuvastatin, and Azithromycin +Rosuvastatin groups. Azithromycin 30 mg/kg/day and Rosuvastatin 2 mg/kg/day were administrated for two weeks by an intragastric tube. Twenty-four hours after the last dose, rats were anesthetized and the following measures were carried out; Electrocardiogram, Blood samples for Biochemical analysis of lactate dehydrogenase (LDH), and creatine phosphokinase (CPK). The animals sacrificed, hearts excised, apical part processed for H&E, immunohistochemical staining, and examined by light microscope. The remaining parts of the heart were collected for assessment of Malondialdehyde (MDA) and Reduced Glutathione (GSH). KEY FINDINGS: The results revealed that Rosuvastatin significantly ameliorates ECG changes, biochemical, and Oxidative stress markers alterations of Azithromycin. Histological evaluation from Azithromycin group showed marked areas of degeneration, myofibers disorganization, inflammatory infiltrate, and hemorrhage. Immunohistochemical evaluation showed significant increase in both Caspase 3 and Tumor necrosis factor (TNF) immune stain. Rosuvastatin treated group showed restoration of the cardiac muscle fibers in H&E and Immunohistochemical results. SIGNIFICANCE: We concluded that Rosuvastatin significantly ameliorates the toxic changes of Azithromycin on the heart.


Subject(s)
Anti-Bacterial Agents/adverse effects , Azithromycin/adverse effects , Cardiotoxicity/prevention & control , Rosuvastatin Calcium/pharmacology , Animals , Anti-Bacterial Agents/administration & dosage , Antioxidants/administration & dosage , Antioxidants/pharmacology , Apoptosis/drug effects , Azithromycin/administration & dosage , COVID-19/drug therapy , Cardiotoxicity/etiology , Disease Models, Animal , Glutathione/metabolism , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Inflammation/chemically induced , Inflammation/prevention & control , Male , Malondialdehyde/metabolism , Oxidative Stress/drug effects , Rats , Rats, Sprague-Dawley , Rosuvastatin Calcium/administration & dosage
7.
Br J Pharmacol ; 177(21): 4975-4989, 2020 11.
Article in English | MEDLINE | ID: covidwho-998827

ABSTRACT

BACKGROUND AND PURPOSE: Resurgence in the use of chloroquine as a potential treatment for COVID-19 has seen recent cases of fatal toxicity due to unintentional overdoses. Protocols for the management of poisoning recommend diazepam, although there are uncertainties in its pharmacology and efficacy in this context. The aim was to assess the effects of diazepam in experimental models of chloroquine cardiotoxicity. EXPERIMENTAL APPROACH: In vitro experiments involved cardiac tissues isolated from rats and incubated with chloroquine alone or in combination with diazepam. In vivo models of toxicity involved chloroquine administered intravenously to pentobarbitone-anaesthetised rats and rabbits. Randomised, controlled treatment studies in rats assessed diazepam, clonazepam and Ro5-4864 administered: (i) prior, (ii) during and (iii) after chloroquine and the effects of diazepam: (iv) at high dose, (v) in urethane-anaesthetised rats and (vi) co-administered with adrenaline. KEY RESULTS: Chloroquine decreased the developed tension of left atria, prolonged the effective refractory period of atria, ventricular tissue and right papillary muscles, and caused dose-dependent impairment of haemodynamic and electrocardiographic parameters. Cardiac arrhythmias indicated impairment of atrioventricular conduction. Studies (i), (ii) and (v) showed no differences between treatments and control. Diazepam increased heart rate in study (iv) and as with clonazepam also prolonged the QTc interval in study (iii). Combined administration of diazepam and adrenaline in study (vi) improved cardiac contractility but caused hypokalaemia. CONCLUSION AND IMPLICATIONS: Neither diazepam nor other ligands for benzodiazepine binding sites protect against or attenuate chloroquine cardiotoxicity. However, diazepam may augment the effects of positive inotropes in reducing chloroquine cardiotoxicity. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc.


Subject(s)
Arrhythmias, Cardiac/chemically induced , Cardiotoxicity/etiology , Chloroquine/poisoning , Diazepam/pharmacology , Animals , Arrhythmias, Cardiac/prevention & control , Benzodiazepinones/pharmacology , COVID-19 , Cardiotoxicity/prevention & control , Clonazepam/pharmacology , Coronavirus Infections/drug therapy , Diazepam/administration & dosage , Dose-Response Relationship, Drug , Drug Overdose , Electrocardiography , Female , Hypokalemia/chemically induced , Male , Pandemics , Pneumonia, Viral/drug therapy , Rabbits , Random Allocation , Rats , Rats, Wistar
8.
BMB Rep ; 53(10): 545-550, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-979311

ABSTRACT

Combination therapy using chloroquine (CQ) and azithromycin (AZM) has drawn great attention due to its potential anti-viral activity against SARS-CoV-2. However, clinical trials have revealed that the co-administration of CQ and AZM resulted in severe side effects, including cardiac arrhythmia, in patients with COVID-19. To elucidate the cardiotoxicity induced by CQ and AZM, we examined the effects of these drugs based on the electrophysiological properties of human embryonic stem cellderived cardiomyocytes (hESC-CMs) using multi-electrode arrays. CQ treatment significantly increased the field potential duration, which corresponds to prolongation of the QT interval, and decreased the spike amplitude, spike slope, and conduction velocity of hESC-CMs. AZM had no significant effect on the field potentials of hESC-CMs. However, CQ in combination with AZM greatly increased the field potential duration and decreased the beat period and spike slope of hESC-CMs when compared with CQ monotherapy. In support of the clinical data suggesting the cardiovascular side effects of the combination therapy of CQ and AZM, our results suggest that AZM reinforces the cardiotoxicity induced by CQ in hESC-CMs. [BMB Reports 2020; 53(10): 545-550].


Subject(s)
Azithromycin/adverse effects , Cardiotoxicity/etiology , Chloroquine/adverse effects , Embryonic Stem Cells/drug effects , Myocytes, Cardiac/drug effects , Action Potentials , Animals , Arrhythmias, Cardiac/chemically induced , Azithromycin/administration & dosage , COVID-19 , Cell Differentiation , Chloroquine/administration & dosage , Coronavirus Infections/complications , Coronavirus Infections/drug therapy , Humans , Mice , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/drug therapy
9.
Food Chem Toxicol ; 145: 111742, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-888511

ABSTRACT

SARS-CoV-2 (Covid-19) infection has recently become a worldwide challenge with dramatic global economic and health consequences. As the pandemic is still spreading, new data concerning Covid-19 complications and related mechanisms become increasingly available. Accumulating data suggest that the incidence of cardiac arrest and its outcome are adversely affected during the Covid-19 period. This may be further exacerbated by drug-related cardiac toxicity of Covid-19 treatment regimens. Elucidating the underlying mechanisms that lead to Covid-19 associated cardiac arrest is imperative, not only in order to improve its effective management but also to maximize preventive measures. Herein we discuss available epidemiological data on cardiac arrest during the Covid-19 pandemic as well as possible associated causes and pathophysiological mechanisms and highlight gaps in evidence warranting further investigation. The risk of transmission during cardiopulmonary resuscitation (CPR) is also discussed in this review. Finally, we summarize currently recommended guidelines on CPR for Covid-19 patients including CPR in patients with cardiac arrest due to suspected drug-related cardiac toxicity in an effort to underscore the most important common points and discuss discrepancies proposed by established international societies.


Subject(s)
Arrhythmias, Cardiac/epidemiology , Arrhythmias, Cardiac/physiopathology , Betacoronavirus , Coronavirus Infections/complications , Heart Arrest/epidemiology , Heart Arrest/physiopathology , Pneumonia, Viral/complications , Arrhythmias, Cardiac/etiology , COVID-19 , Cardiopulmonary Resuscitation/standards , Cardiotoxicity/epidemiology , Cardiotoxicity/etiology , Cardiotoxicity/physiopathology , Coronavirus Infections/drug therapy , Disease Transmission, Infectious/prevention & control , Heart Arrest/etiology , Humans , Pandemics , Pneumonia, Viral/drug therapy , SARS-CoV-2
10.
Ann Med ; 53(1): 117-134, 2021 12.
Article in English | MEDLINE | ID: covidwho-889359

ABSTRACT

Hydroxychloroquine, initially used as an antimalarial, is used as an immunomodulatory and anti-inflammatory agent for the management of autoimmune and rheumatic diseases such as systemic lupus erythematosus. Lately, there has been interest in its potential efficacy against severe acute respiratory syndrome coronavirus 2, with several speculated mechanisms. The purpose of this review is to elaborate on the mechanisms surrounding hydroxychloroquine. The review is an in-depth analysis of the antimalarial, immunomodulatory, and antiviral mechanisms of hydroxychloroquine, with detailed and novel pictorial explanations. The mechanisms of hydroxychloroquine are related to potential cardiotoxic manifestations and demonstrate potential adverse effects when used for coronavirus disease 2019 (COVID-19). Finally, current literature associated with hydroxychloroquine and COVID-19 has been analyzed to interrelate the mechanisms, adverse effects, and use of hydroxychloroquine in the current pandemic. Currently, there is insufficient evidence about the efficacy and safety of hydroxychloroquine in COVID-19. KEY MESSAGES HCQ, initially an antimalarial agent, is used as an immunomodulatory agent for managing several autoimmune diseases, for which its efficacy is linked to inhibiting lysosomal antigen processing, MHC-II antigen presentation, and TLR functions. HCQ is generally well-tolerated although severe life-threatening adverse effects including cardiomyopathy and conduction defects have been reported. HCQ use in COVID-19 should be discouraged outside clinical trials under strict medical supervision.


Subject(s)
Antimalarials/therapeutic use , Cardiotoxicity/etiology , Coronavirus Infections/drug therapy , Hydroxychloroquine/therapeutic use , Pneumonia, Viral/drug therapy , Antimalarials/pharmacology , COVID-19 , Clinical Trials as Topic , Humans , Hydroxychloroquine/pharmacology , Pandemics
11.
BMB Rep ; 53(10): 545-550, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-783912

ABSTRACT

Combination therapy using chloroquine (CQ) and azithromycin (AZM) has drawn great attention due to its potential anti-viral activity against SARS-CoV-2. However, clinical trials have revealed that the co-administration of CQ and AZM resulted in severe side effects, including cardiac arrhythmia, in patients with COVID-19. To elucidate the cardiotoxicity induced by CQ and AZM, we examined the effects of these drugs based on the electrophysiological properties of human embryonic stem cellderived cardiomyocytes (hESC-CMs) using multi-electrode arrays. CQ treatment significantly increased the field potential duration, which corresponds to prolongation of the QT interval, and decreased the spike amplitude, spike slope, and conduction velocity of hESC-CMs. AZM had no significant effect on the field potentials of hESC-CMs. However, CQ in combination with AZM greatly increased the field potential duration and decreased the beat period and spike slope of hESC-CMs when compared with CQ monotherapy. In support of the clinical data suggesting the cardiovascular side effects of the combination therapy of CQ and AZM, our results suggest that AZM reinforces the cardiotoxicity induced by CQ in hESC-CMs. [BMB Reports 2020; 53(10): 545-550].


Subject(s)
Azithromycin/adverse effects , Cardiotoxicity/etiology , Chloroquine/adverse effects , Embryonic Stem Cells/drug effects , Myocytes, Cardiac/drug effects , Action Potentials , Animals , Arrhythmias, Cardiac/chemically induced , Azithromycin/administration & dosage , COVID-19 , Cell Differentiation , Chloroquine/administration & dosage , Coronavirus Infections/complications , Coronavirus Infections/drug therapy , Humans , Mice , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/drug therapy
12.
Clin Transl Sci ; 14(1): 163-169, 2021 01.
Article in English | MEDLINE | ID: covidwho-751768

ABSTRACT

The recent empirical use of hydroxychloroquine (HCQ) in coronavirus disease 2019 (COVID-19) revived the interest in its cardiac toxicity, increasingly sidelined over time. We aimed to assess and compare the profile of cardiac adverse drug reactions (CADRs) associated with HCQ before and during COVID-19. We performed a retrospective comparative observational study using the French Pharmacovigilance network database between 1985 and May 2020 to assess all postmarketing CADRs associated with HCQ notified before COVID-19 in its approved indications for lupus and rheumatoid arthritis (preCOV), and those concerning its empirical use in COVID-19 (COV). Eighty-five CADR in preCOV were compared with 141 CADRs in COV. The most common CADR of preCOV were cardiomyopathies (42.4%) and conduction disorders (28.2%), both statistically more frequent than in COV (P < 0.001). COV notifications significantly highlighted repolarization and ventricular rhythm disorders (78.0%, P < 0.001) as well as sinus bradycardias (14.9%, P = 0.01) as compared with preCOV. Estimated incidence of CADR was significantly higher among patients exposed to off-label use of HCQ in COVID-19 (2.9%) than before COVID-19 in its approved indications (0.01%, P < 0.001). The use of HCQ in COVID-19 sheds a new light on the spectrum of its cardiac toxicity. This fosters the value of a closer monitoring of all patients treated with HCQ, regardless of its indication, and the importance of an update of its summary of product characteristics.


Subject(s)
COVID-19/drug therapy , Cardiotoxicity/etiology , Hydroxychloroquine/adverse effects , SARS-CoV-2 , Adult , Aged , Cardiomyopathies/chemically induced , Female , Heart Conduction System/drug effects , Humans , Male , Middle Aged , Retrospective Studies
13.
Eur J Clin Pharmacol ; 77(1): 13-24, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-710271

ABSTRACT

INTRODUCTION: Many concerns still exist regarding the safety of hydroxychloroquine (HCQ) in the treatment of Coronavirus Disease 2019 (COVID-19). OBJECTIVES: The purpose of this study was to evaluate the safety of HCQ in the treatment of COVID-19 and other diseases by performing a systematic review and meta-analysis. METHODS: Randomized controlled trials (RCTs) reporting the safety of HCQ in PubMed, Embase, and Cochrane Library were retrieved starting from the establishment of the database till June 5, 2020. Literature screening, data extraction, and assessment of risk bias were performed independently by two reviewers. RESULTS: We identified 53 eligible studies involving 5496 patients. The meta-analysis indicated that the risk of adverse effects (AEs) in the HCQ group was significantly increased compared with that in the control group (RD 0.05, 95%CI, 0.02 to 0.07, P = 0.0002), and the difference was also statistically significant in the COVID-19 subgroup (RD 0.15, 95%CI, 0.07 to 0.23, P = 0.0002) as well as in the subgroup for other diseases (RD 0.03, 95%CI, 0.01 to 0.04, P = 0.003). CONCLUSIONS: HCQ is associated with a high total risk of AEs compared with the placebo or no intervention in the overall population. Given the small number of COVID-19 participants included, we should be cautious regarding the conclusion stating that HCQ is linked with an increase incidence of AEs in patients with COVID-19, which we hope to confirm in the future through well-designed and larger sample size studies.


Subject(s)
COVID-19/drug therapy , Hydroxychloroquine/adverse effects , SARS-CoV-2 , Cardiotoxicity/etiology , Gastrointestinal Tract/drug effects , Humans , Outcome Assessment, Health Care , Publication Bias , Skin/drug effects
14.
Pharmacotherapy ; 40(9): 978-983, 2020 09.
Article in English | MEDLINE | ID: covidwho-648736

ABSTRACT

Hydroxychloroquine combined with azithromycin has been investigated for activity against coronavirus disease 2019 (COVID-19), but concerns about adverse cardiovascular (CV) effects have been raised. This study evaluated claims data to determine if risks for CV events were increased with hydroxychloroquine alone or combined with azithromycin. We identified data from 43,752 enrollees that qualified for analysis. The number of CV events increased by 25 (95% confidence interval [CI]: 8, 42, p=0.005) per 1000 people per year of treatment with hydroxychloroquine alone compared with pretreatment levels and by 201 (95% CI: 145, 256, p<0.001) events per 1000 people per year when individuals took hydroxychloroquine and azithromycin. These rates translate to an additional 0.34 (95% CI: 0.11, 0.58) CV events per 1000 patients placed on a 5-day treatment with hydroxychloroquine monotherapy and 2.75 (95% CI: 1.99, 3.51) per 1000 patients on a 5-day treatment with both hydroxychloroquine and azithromycin. The rate of adverse events increased with age following exposure to hydroxychloroquine alone and combined with azithromycin. For females aged 60 to 79 years prescribed hydroxychloroquine, the rate of adverse CV events was 0.92 per 1000 patients on 5 days of therapy, but it increased to 4.78 per 1000 patients when azithromycin was added. The rate of adverse CV events did not differ significantly from zero for patients 60 years of age or younger. These data suggest that hydroxychloroquine with or without azithromycin is likely safe in individuals under 60 years of age if they do not have additional CV risks. However, the combination of hydroxychloroquine and azithromycin should be used with extreme caution in older patients.


Subject(s)
Azithromycin/adverse effects , COVID-19/drug therapy , Cardiotoxicity/etiology , Hydroxychloroquine/adverse effects , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Azithromycin/administration & dosage , Cardiotoxicity/epidemiology , Cardiovascular Diseases/chemically induced , Cardiovascular Diseases/epidemiology , Child , Child, Preschool , Databases, Factual , Drug Therapy, Combination , Female , Humans , Hydroxychloroquine/administration & dosage , Infant , Infant, Newborn , Male , Middle Aged , Risk Factors , Sex Factors , Young Adult
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